Treating fibromyalgia and chronic fatigue syndrome

ABSTRACT

The present invention provides for methods for the treatment of fibromyalgia syndrome or chronic fatigue syndrome by the administration of heterocyclic amine-type compounds or a salt of any said compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of the following U.S. provisionalapplications: Ser. No. 60/198,959 filed Apr. 1, 2000 and Ser. No.60/200,569 filed Apr. 28, 2000, under 35 U.S.C. §119(e)(1).

FIELD OF THE INVENTION

The present invention relates to the use of neuromuscular agents, andthe pharmacologically acceptable salts thereof, for the treatment ofnervous system disorders, and more particularly to the use of compoundsof U.S. Pat. Nos. 5,273,975, 5,436,240, 5,594,024, 5,462,947, and4,526,892 for the treatment of symptoms of fibromyalgia syndrome andchronic fatigue syndrome.

BACKGROUND OF THE INVENTION

Chronic fatigue syndrome (CFS), also referred to as chronic fatigueimmune disorders syndrome, yuppie flu; fatigue-chronic, and chronicfatigue and immune dysfunction syndrome, is a clinically definedcondition characterized by profound tiredness or fatigue. In addition,patients with CFS generally report various nonspecific symptoms,including weakness, muscle aches and pains, excessive sleep, malaise,fever, sore throat, tender lymph nodes, impaired memory and/or mentalconcentration, insomnia, and depression. The exact cause of CFS isunknown and, to date, there are no specific tests to confirm thediagnosis of CFS, though a variety of tests are usually done to excludeother possible causes of the symptoms.

Fibromyalgia syndrome (FMS), also referred to as fibromyalgia,fibromyositis, fibrositis, or myofasical pain syndrome, is a rheumaticcondition generally characterized by widespread pain in fibrous tissues,muscles, tendons, and other connective tissues, fatigue, headaches, lackof restorative sleep, and numbness. Thus, FMS shares many clinicalfeatures with CFS. Similar to CFS, there are no specific diagnostictests for FMS.

Many medications are commonly used to treat CFS and FMS. Examples of themore common medications include hypnotics, immune suppressants, variousother prescribed medications, and an array of non-prescriptionmedications. Examples of other prescription drugs include opioidantagonists, sodium retention agents/beta blockers, calcium channelblockers/histamine blockers, anti-depressants, allergy medications, andacute anxiety medications. However, there are no known medications thatpermanently resolve the symptoms of either CFS or FMS. In addition, manyof the currently used medications produce side effects ranging from mildside effects, e.g., drowsiness, dizziness, and nausea to serious sideeffects, e.g., addiction and liver damage.

Accordingly, there is clearly a need for better treatments for chronicfatigue syndrome and fibromyalgia. Now, the present invention revealsseveral compounds that can be formulated into useful therapeutictreatments for these conditions.

SUMMARY OF THE INVENTION

Disclosed is a method of treating symptoms of fibromyalgia syndrome orchronic fatigue syndrome which comprises administering to a patient inneed of treatment a therapeutically effective amount of a heterocyclicamine-type compound of formula (A),

or a pharmaceutically acceptable salt thereof, wherein:

R₁, R₂, and R₃ are independently hydrogen, C₁₋₆ alkyl, C₃₋₅ alkenyl,C₃₋₅ alkynyl, C₃₋₇ cycloalkyl, C₄₋₁₀ cycloalkyl- or phenyl-substitutedC₁₋₆ alkyl, or R₁ and R₂ are joined to form a C₃₋₇ cyclic amine whichcan contain additional heteroatoms and/or unsaturation;

X is hydrogen, C₁₋₆ alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide,carboxyl, or carboalkoxyl;

A is CH, CH₂, CH-halogen, CHCH₃, C═O, C═S, C—SCH₃, C═NH, C—NH₂, C—NHCH₃,C—NHCOOCH₃, C—NHCN, SO₂, or N;

B is CH₂, CH, CH-halogen, C═O, N, NH or N—CH₃, or O;

n is 0 or 1; and

D is CH, CH₂, CH-halogen, C═O, O, N, NH, or N—CH₃.

Preferred compounds of formula (A) include(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one(uninverted CAS name) and(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione,and their pharmaceutically acceptable salts.

Also disclosed is a method of treating symptoms of fibromyalgia syndromeor chronic fatigue syndrome which comprises administering to a patientin need of treatment a therapeutically effective amount of a substitutedphenylazacycloalkane-type compound of formula (B),

or pharmaceutically acceptable salts thereof, wherein:

n is 0-3;

R¹ and R² are independently H (provided only one is H at the same time),—OH (provided R⁴ is other than hydrogen), CN, CH₂CN, 2- or 4-CF₃,CH₂CF₃, CH₂CHF₂, CH═CF₂, (CH₂)₂CF₃, ethenyl, 2-propenyl, OSO₂CH₃,OSO₂CF₃, SSO₂CF₃, COR⁴, COOR⁴, CON(R⁴)₂, SO_(x)CH₃ (where, x is 0-2),SO_(x)CF₃, O(CH₂)_(x)CF₃, SO₂N(R⁴)₂, CH═NOR⁴, COCOOR⁴, COCOON(R⁴)₂, C₁₋₈alkyls, C₃₋₈ cycloalkyls, CH₂OR⁴, CH₂(R⁴)₂, NR⁴SO₂CF₃, NO₂, halogen, aphenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole,thiazole, N-pyrroline, triazole, tetrazole or pyridine;

R³ is hydrogen, CF₃, CH₂CF₃, C₁-C₈ alkyl, C₃-C₈ cycloalkyl, C₄-C₉cycloalkyl-methyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl, 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl, —(CH₂)_(m)—R⁵ (where m is 1-8), CH₂SCH₃ or a C₄-C₈alkyl bonded to said nitrogen and one of its adjacent carbon atomsinclusive to form a cyclic structure;

R⁴ is independently hydrogen, CF₃, CH₂CF₃, C_(1-C) ₈ alkyl, C_(3-C) ₈cycloalkyl, C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, —(CH₂)_(m)—R⁵ where m is1-8;

R⁵ is phenyl, phenyl (substituted with a CN, CF₃, CH₂CF₃, C₁-C₈ alkyl,C₃-C₈ cycloalkyl, C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl, C_(2-C) ₈alkynyl), 2-thiophenyl, 3-thiophenyl, —NR⁶CONR⁶R⁷, or —CONR⁶R⁷;

R⁶ and R⁷ are independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl; and with theproviso that when R¹ is 2—CN or 4—CN, R² is H, R³ is n-Pr and n is 1 or3 then such compound is a pure enantiomer.

Preferred compounds of formula (B) include(3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride,(3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide, and(3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine (2E)-2-butenedioate(1:1).

Further disclosed is a method of treating symptoms of fibromyalgiasyndrome or chronic fatigue syndrome which comprises administering to apatient in need of treatment a therapeutically effective amount of acabergoline-type compound, or pharmaceutically acceptable salts thereof,with the preferred compound of this class being cabergoline.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to therapies for fibromyalgia (FMS) andchronic fatigue syndrome (CFS), and more particularly to the use ofthree broad classes of compounds having dopamine receptor activities fortreating the symptoms of FMS and CFS. The useful compounds identifiedfor the method of the present invention are described in two ways, withgeneric descriptions of completely enabled and disclosed groups ofcompounds and with detailed individually described compound structuresand names. One class of compounds useful for treating symptoms of CFSand FMS in the present invention are those compounds, orpharmaceutically acceptable salts thereof, disclosed generically orspecifically in U.S. Pat. Nos. 5,273,975 and 5,436,240. These compoundsare generically referred to as heterocyclic amine type compounds and arestructurally represented by formula (A),

wherein:

R₁, R₂, and R₃ are independently and are hydrogen, C₁₋₆ alkyl, C₃₋₅alkenyl, or C₃₋₅ alkynyl, C₃₋₇ cycloalkyl, C₄₋₁₀ cycloalkyl- or phenyl-substituted C₁₋₆ alkyl, or R₁ and R₂ are joined to form a C₃₋₇ cyclicamine which can contain additional heteroatoms and/or unsaturation;

X is hydrogen, C₁₋₆ alkyl halogen, hydroxy, alkoxy, cyano, carboxamide,carboxyl, or carboalkoxyl;

A is CH, CH₂, CH-halogen, CHCH₃, C═O, C═S, C—SCH₃, C═NH, C—NH₂, C—NHCH₃,C—NHCOOCH₃, or C—NHCN, SO₂, or N;

B is CH₂, CH, CH-halogen, C═O, N, NH, N—CH₃ or O;

n is 0 or 1; and

D is CH, CH₂, CH-halogen, C═O, O, N, NH or N—CH₃.

The methods of making the compounds and the pharmaceuticallypreparations are described in U.S. Pat. Nos. 5,273,975 and 5,436,240,and in International Patent Application WO 00/40226. The full disclosureof the above-cited U.S. Pat. Nos. 5,273,975 and 5,436,240 andInternational Patent Application WO 00/40226 is incorporated herein byreference.

An especially preferred compound of formula (A) in the present inventionis a compound of formula (Aa),

or pharmaceutically acceptable salt thereof. The compound name for thecompound of formula (Aa) is(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one(uninverted CAS name) or(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(Generated by ACD/Name software).

It is preferred that(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-onebe present in a pharmaceutically acceptable salt. Suitablepharmaceutically acceptable salts include salts of both inorganic andorganic acids; examples include without limitation salts of thefollowing acids: hydrochloric, hydrobromic, sulfuric, phosphoric,nitric, citric, methanesulfonic, CH₃—(CH₂)_(n1)—COOH where n₁ is 0 thru4, HOOC—(CH₂)n₁—COOH where n is as defined above, HOOC—CH═CH—COOH, andφ—COOH. For other acceptable salts, see Int. J. Pharm., 33, 201-217(1986). A particularly preferred salt of(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-oneis the maleate. i.e. (Z)-2-butenedioate, salt, which is(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-one(Z)-2-butenedioate (1:1). The (Z)-2-butenedioate salt is shown asformula (Ab):

Another group of compounds within the generic formula of theheterocyclic amine-type compounds shown above, are selected heterocyclicamine compounds, the most preferred being(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione,a compound of the formula (Ac) below, also referred to herein at formula(VIII),

or pharmaceutically acceptable salts thereof.

U.S. Pat. No. 5,273,975 generically discloses and claims(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione,but does not give an example or specific mention of this compound.(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(VIII) is preferably made from the corresponding non-thio analog,(5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one(VII). A preferred process of making(5R)-(Methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one(VII) is illustrated in PREPARATION 1 and EXAMPLES 1-6, as well as CHARTA. The preferred method of transforming(5R)-(methylamino)-5,6-dihydro-4H-imidao(4,5,1-ij)quinolin-(2H)-one(VII) into(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(VIII) is set forth in EXAMPLE 8.

It is preferred that(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(IX) be present as a pharmaceutically acceptable salt. Pharmaceuticallyacceptable salts include salts of both inorganic and organic acids. Thepreferred pharmaceutically acceptable salts include salts of thefollowing acids hydrochloric, hydrobromic, sulfuric, phosphoric, nitric,citric, methanesulfonic CH₃—(CH₂)_(n1)—COOH where n₁ is 0 thru 4,HOOC—(CH₂)n₁—COOH where n is as defined above, HOOC—CH═CH—COOH, φ-COOH.For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986). Itis more preferred that(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionebe present as the maleate salt, which is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionemaleate. The maleate salt is shown below as formula (Ad) or formula(IX):

Conventional pharmaceutical preparations can be used for theheterocyclic amine-type compounds, e.g., consisting essentially of aninert pharmaceutical carrier and an effective dose of the activesubstance. Suitable dosages forms include without limitation plain orcoated tablets, capsules, lozenges, powders, solutions, suspensions,emulsions, syrups, suppositories, transdermal patch, etc., with tabletbeing the preferred dosage form.

The effective dose range for oral administration of a heterocyclicamine-type compound is from about 0.30 through about 50.0mg/dose/patient orally. Patients with milder forms of FMS or CFS wouldbe expected to need less drug, while patients with more severe forms ofthe disease may be expected to need more drug. The dosages to be givento a particular patient should be easily determined by a skilledphysician with experience in prescribing biologically active drugsdesigned to modulate central nervous system, movement and relatedpsychological and physiological disorders of the type described here.Normally the drug is given once a day or twice a day; it may be giveneven less often for some patients.

Another class of compounds useful in the present invention are thosecompounds, or pharmaceutically acceptable salts thereof, disclosedgenerically or specifically in U.S. Pat. Nos. 5,594,024 and 5,462,947,both incorporated by reference herein. These compounds are genericallyreferred to as substituted phenylazacycloalkane-type compounds and arestructurally represented by formula (B),

wherein:

n is 0-3;

R¹ and R² are independently H (provided only one is H at the same time),—OH (provided R⁴ is other than hydrogen), CN, CH₂CN, 2- or 4—CF₃,CH₂CF₃, CH₂CHF₂, CH═CF₂, (CH₂)₂CF₃, ethenyl, 2-propenyl, OSO₂CH₃,OSO₂CF₃, SSO₂CF₃, COR⁴, COOR⁴, CON(R⁴)₂, SO_(x)CH₃ (where, x is 0-2),SO_(x)CF₃, O(CH₂)_(x)CF₃, SO₂N(R⁴)₂, CH═NOR⁴, COCOOR⁴, COCOON(R⁴)₂, C₁₋₈alkyls, C₃₋₈ cycloalkyls, CH₂OR⁴, CH₂(R⁴)₂, NR⁴SO₂CF₃, NO₂, halogen, aphenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole,thiazole, N-pyrroline, triazole, tetrazole or pyridine;

R³ is hydrogen, CF₃, CH₂CF₃, C₁—C₈ alkyl, C₃—C₈ cycloalkyl, C₄—C₉cycloalkyl-methyl, C₂—C₈ alkenyl, C₂-C₈ alkynyl, 3,3,3-trifluoropropyl,4,4,4-trifluorobutyl, —(CH₂)_(m)—R⁵ (where m is 1-8), CH₂SCH₃ or a C₄-C₈alkyl bonded to said nitrogen and one of its adjacent carbon atomsinclusive to form a cyclic structure;

R⁴ is independently hydrogen, CF₃, CH₂CF₃, C₁-C₈ alkyl, C₃-C₈cycloalkyl, C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,3,3,3-trifluoropropyl, 4,4,4-trifluoro-butyl, —(CH₂)_(m)—R⁵ where m is1-8;

R⁵ is phenyl, phenyl (substituted with a CN, CF₃, CH₂CF₃, C₁-C₈ alkyl,C₃-C₈ cycloalkyl, C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl, C₂-C₈alkynyl), 2-thiophenyl, 3-thiophenyl, —NR⁶CONR⁶R⁷, or —CONR⁶R⁷;

R⁶ and R⁷ are independently hydrogen, C₁-C₈ alkyl, C₃-C₈ cycloalkyl,C₄-C₉ cycloalkyl-methyl, C₂-C₈ alkenyl or C₂-C₈ alkynyl; and with theproviso that when R¹ is 2—CN or 4—CN, R² is H, R³ is n—Pr and n is 1 or3 then such compound is a pure enantiomer.

Also useful in the present invention are pharmaceutically acceptablesalts of compounds of formula (B), those salts being disclosed in U.S.Pat. Nos. 5,462,947 and 5,594,024, both incorporated herein byreference. Both organic and inorganic acids can be employed to formpharmaceutically acceptable salts; illustrative acids include sulfuric,nitric, phosphoric, hydrochloric, citric, acetic, lactic,ethanedisulfonic, sulfamic, succinic, cyclohexylsulfamic, fumaric,maleic, and benzoic acids. These salts are readily prepared by methodsknown in the art.

A particularly suitable compound of formula (B) in the present inventionis (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride(uninverted CAS name) or OSU 6162 or(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrochloride(Generated by ACD/Name software), and is represented by formula (Ba):

Another particularly suitable compound of formula (B) in the presentinvention is (3S)-3-[3-(Methylsulfonyl)phenyl]-1-propylpiperidinehydrobromide (uninverted CAS name) or(3S)-3-[3-(methylsulfonyl)phenyl]-1-propylpiperidine hydrobromide(Generated by ACD/Name software), and is represented by formula (Bb):

Yet another particularly suitable compound of formula (B) in the presentinvention is (3S)-3-[3-Methylsulfonyl)phenyl]-1-propylpiperidine(2E)-2-butenedioate (1:1) (uninverted CAS name) or (S)-OSU6162, and isrepresented by formula (Bc):

The methods of preparing these compounds, and formulations andmedicaments of the same, are described in U.S. Pat. Nos. 5,594,024 and5,462,947, both incorporated herein by reference.

Conventional pharmaceutical preparations can be used for the substitutedphenylazacycloalkane-type compounds, e.g., consisting essentially of aninert pharmaceutical carrier and an effective dose of the activesubstance; e.g., plain or coated tablets, capsules, lozenges, powders,solutions, suspensions, emulsions, syrups, suppositories, transdermalpatch, etc. Preferred dosage forms are tablets.

The effective dose range for oral administration of a substitutedphenylazacycloalkane-type compound is from about 10 to about 1000mg/dose/patient once or twice a day. The dosage and dose frequency for aparticular patient should be easily determined by a skilled physicianwith experience in prescribing biologically active drugs designed tomodulate central nervous system, movement and related psychological andphysiological disorders of the type described here. While normally thedrug may be given once a day or twice a day, it may be given even lessoften for some patients.

A further class of compounds useful in the present invention are thosecompounds, or pharmaceutically acceptable salts thereof, disclosedgenerically or specifically in U.S. Pat. No. 4,526,892, the fulldisclosure of which is incorporated herein by reference. These compoundsare generically referred to as cabergoline-type compounds. The preferredcompound in this class is cabergoline itself, or its pharmaceuticallyacceptable salts. The chemical name for cabergoline is1-((6-allylergolin-8β-yl)-carbony.)-1-(3-(dimethylamino)propyl)-3-ethylurea and the structure ofcarbergoline is represented by formula (C):

Cabergoline is the generic name for the active ingredient in DOSTINEX®or CABASER® Tablets, which are marketed by Pharmacia & Upjohn, Inc. inthe United States, Europe and Latin America as a treatment forhyperprolactinemic disorders and Parkinson's disease. The synthesis anduse of cabergoline is disclosed and claimed in U.S. Pat. No. 4,526,892,which is incorporated herein by reference.

Conventional pharmaceutical preparations can be used for cabergoline,e.g., consisting essentially of an inert pharmaceutical carrier and aneffective dose of the active substance, e.g., plain or coated tablets,capsules, lozenges, powders, solutions, suspensions, emulsions, syrups,suppositories, etc., with tablet being the preferred dosage form.

A package insert describing CABASER®, its pharmacokinetics, clinicalstudies, indications and usage, contraindication and warnings, andParkinson's disease patients is provided by Pharmacia & Upjohn, Inc.This package insert and its descriptions are incorporated by referenceinto this application.

The effective dose range for cabergoline is from about 0.01 to about10.0 mg/dose/patient, preferably from about 0.25 to about 10.0mg/dose/patient, more preferably from about 1 to about 6mg/dose/patient, and even more preferably from about 1 to about 2mg/dose/patient orally. At these dose levels above, cabergoline istypically administered once or twice a day; however, for some patientsthe dose frequency may be reduced to three times a week, two times aweek or even once a week. The combination of dosage levels and dosefrequency for a particular patient may be readily adjusted by thetreating physician.

The dose response to cabergoline in terms of efficacy and side effectsappears to be mainly linked to individual sensitivity. Under somecircumstances and with the appropriate patients, dose optimization maybe obtained, for example, by administering a low initial dose ofcabergoline to the patient at a dose of 0.5 to 1 mg/patient/day andadjusting the dose upward at weekly intervals to an optimal therapeuticdosage of 2, 4, 6, 8 or 10 mg/patient/day. Patients with milder forms ofthe disease would be expected to need less drug. For example, in somecases a dose of 0.05, 0.1 or even 0.25 mg/patient may be adequate.Patients with more severe forms of the disease and those who have beentreated with other dopaminergic agents may be expected to need moredrug. The precise dosage would be readily determined by the treatingphysician evaluating such factors as the progression of the state of thedisease, the weight and age of the patient, whether and to what extentother drugs such as L-Dopa or levodopa were administered, and other suchfactors as are typically evaluated by a physician before determining thedosage of a CNS drug to a patient.

DEFINITIONS AND CONVENTION

The definitions and explanations below are for the terms as usedthroughout this entire document including both the specification and theclaims.

DEFINITIONS

All temperatures are in degrees Celsius.

TLC refers to thin-layer chromatography.

HPLC refers to high pressure liquid chromatography.

Saline refers to an aqueous saturated sodium chloride solution.

Chromatography (column and flash chromatography) refers topurification/separation of compounds expressed as (support, eluent). Itis understood that the appropriate fractions are pooled and concentratedto give the desired compound(s).

IR refers to infrared spectroscopy.

CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts arereported in ppm (δ) downfield from TMS.

NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemicalshifts are reported in ppm (δ) downfield from tetramethylsilane.

−φ refers to phenyl (C₆H₅).

[α]_(D) ²⁵ refers to the angle of rotation of plane polarized light(specific optical rotation) at 25° with the sodium D line (589A).

MS refers to mass spectrometry expressed as m/e, m/z or mass/chargeunit. [M+H]⁺ refers to the positive ion of a parent plus a hydrogenatom. EI refers to electron impact. CI refers to chemical ionization FABrefers to fast atom bombardment.

Pharmaceutically acceptable refers to those properties and/or substanceswhich are acceptable to the patient from a pharmacological/toxicologicalpoint of view and to the manufacturing pharmaceutical chemist from aphysical/chemical point of view regarding composition, formulation,stability, patient acceptance and bioavailability.

When solvent pairs are used, the ratios of solvents used arevolume/volume (v/v).

When the solubility of a solid in a solvent is used the ratio of thesolid to the solvent is weight/volume (wt/v).

EXAMPLES

Without further elaboration, it is believed that one skilled in the artcan, using the preceding description, practice the present invention toits fullest extent. The following detailed examples describe how toprepare the various compounds and/or perform the various processes ofthe invention and are to be construed as merely illustrative, and notlimitations of the preceding disclosure in any way whatsoever. Thoseskilled in the art will promptly recognize appropriate variations fromthe procedures both as to reactants and as to reaction conditions andtechniques.

PREPARATION 1 (R)-Naproxen chloride

R-naproxen (Can. J. Chem., 72(1), 142-5 (1994), 260 g), methylenechloride (3.33 kg) and DMF (8.2 ml) are added to a reactor. Oxalylchloride (191.8 g) is slowly added to this mixture. After addition ofthe oxalyl chloride, the slurry is stirred at 5 to 10° and then slowlywarmed to 20-25°. The resulting mixture is concentrated to remove themethylene chloride, branched octane is added to the concentrate and themixture is again concentrated. More branched octane is added to theconcentrate and the mixture is cooled to 0° and stirred to crystallize.The crystal slurry is filtered, the crystal cake is washed with octaneand dried at 20-25° to obtain the title compound.

The filtrate from the first crop is concentrated, branched octane isadded and the mixture is cooled and stirred to obtain a second crop ofthe title compound. The slurry is filtered, the crystal cake is washedwith branched octane and dried at 20-25°.

EXAMPLE 1 1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II)

A mixture of 4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (I, J. HeterocyclicChem.,19, 837-49 (1982), 1.0 g, 5.8 mmol) in DMF (10 ml) is cooled to 0°and treated with potassium t-butoxide in THF (1.98 M, 3.2 ml, 6.3 mmol)maintaining the reaction temperature at 0°. The resulting mixture isstirred at 0° for 10 minutes. Benzyl bromide (0.73 ml, 6.1 mmol) is thenadded while maintaining the reaction temperature at methyl t-butyl ether(MTBE) from water followed by several water washes. The MTBE phase isconcentrated under reduced pressure. The concentrate is cooled to 0°,filtered and washed two times with 0° MTBE. The product is dried at 50°under reduced pressure with a nitrogen purge to give the title compound,CMR (CDCl₃, 100 MHz) 153.78, 136.44, 128.69, 127.67, 127.60, 126.73,125.86, 122.90, 122.78, 121.28, 116.92, 116.17, 108.36, 44.95 and 42.37δ.

EXAMPLE 2(5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (III)

1-Benzyl-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (II, EXAMPLE 1, 240 g),acetonitrile (1.086 kg), water (227 ml) and fluoboric acid (48.5%, 13.4g) are mixed and cooled to 0 to 5°. Dibromantin (163.5 g) is slurriedinto acetonitrile and is added to the reaction mixture. The reaction iscarried out for about 3 hr at 0 to 5°. After the reaction is complete,methyl t-butyl ether is added over about 45 minutes keeping the reactiontemperature in the pot below 10°. The slurry is cooled to −10 to −15°,stirred for an hour and then filtered. The product is washed withprecooled methyl t-butyl ether, dried with 40° nitrogen to give thetitle compound, CMR (CDCl₃) 156.0, 137.8, 130.5, 129.6, 129.3, 129.1,126.6, 123.6, 122.5, 119.6, 110.4, 69.9, 49.6, 47.7, 46.9 and 43.8 δ.

EXAMPLE 3 (5S,6S)-1-Benzyl-5-bromo-2oxo1,2,5,6tetrahydro4Himidazo[4,5,1ij]quinolin6yl(2R)-(6-methoxy-2-naphthyl)propanoate(IVA) and(5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-(6-methoxy-2-naphthyl)propanoate (IVB)

(5R,6R)-1-Benzyl-5-bromo-6-hydroxy-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(III, EXAMPLE 2, 143 g), methylene chloride (3,136 g), N-methylmorpholine (100.2 g) and 4-dimethylaminopyridine (497 mg) are added tothe reactor and the mixture is cooled to 0 to 5°. (R)-Naproxen chloride(PREPARATION 1, 118.5 g) dissolved in methylene chloride (694 ml) isadded to the reactor over about 1 hr and the mixture is stirred at 0 to5° to complete the reaction. If necessary, additional naproxen chlorideis added to complete the reaction. Potassium carbonate solution dilutedwith water is added to the mixture. The aqueous phase is extracted withmethylene chloride and the combined methylene chloride phase is washedwith water. The washed mixture is concentrated by vacuum distillationand solvent exchange with ethyl acetate is performed. The concentrate iscooled to −10° and stirred. The crystal slurry is filtered and thecrystal cake is washed with precooled methyl t-butyl ether and dried at50° to give the title compound in solid form,(5S,6S)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVA), CMR (CDCl₃) δ173.2,157.8, 153.4, 136.1, 134.6, 133.7, 129.2, 128.8, 127.8, 127.8, 127.6,127.2, 125.9, 125.9, 125.6, 121.5, 121.4, 119.1, 113.2, 109.0, 105,105.6, 69.2, 55.3, 45.4, 45.2, 42.5, 41.7 and 18.3.

The undesired isomer,(5R,6R)-1-benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R)-2-(6-methoxy-2-naphthyl)propanoate (IVB) is in the filtrate and canbe recovered by means well known to those skilled in the art,(5R,6R)-1-benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one,CMR (CDCl₃) δ 173.2, 157.9, 153.4, 136.1, 135.0, 133.8, 129.2, 128.9,128.8, 127.8, 127.6, 127.4, 125.8, 125.8, 125.7, 121.6, 121.5, 119.3,113.1, 109.1, 105.7,68.7, 55.3, 45.3, 45.2, 42.2, 41.3 and 18.1.

EXAMPLE 4(5R,6R)-1-Benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(V)

(5S,6S)-1-Benzyl-5-bromo-2-oxo-1,2,5,6-tetrahydro-4H-imidazo[4,5,1-ij]quinolin-6-yl(2R-2-(6-methoxy-2-naphthyl)propanoate (IVA, EXAMPLE 3, 110 g) isslurried in acetonitrile (1,297 g). After adding aqueous methylamine (40wt %, 327 g) the reaction is carried out for about 12 hr at about 30°.After the reaction is complete, the mixture is concentrated and ethylacetate is added. Dilute hydrochloric acid is added to make thewater-soluble salt of the title compound. The byproduct (R-naproxenmethylamide impurity) is insoluble in water and stays in the ethylacetate phase. Further extractions and washes are carried out for betterseparation of the (naproxen acetamide) impurity with minimum loss of thedesired product. Then a sodium hydroxide solution is added to theaqueous phase and the hydrochloride salt of the title compound isconverted to the free base. The free base is less soluble in water andis extracted into ethyl acetate. The product mixture is concentrated andsolvent exchanged with ethyl acetate to remove water. Crystallization isperformed by adding branched chain octane and cooling the mixture. Theresulting slurry is filtered, washed and dried at 50° to give the titlecompound, CMR (CDCl₃) δ 153.7, 136.3, 128.7, 127.8, 127.7, 125.7, 121.3,119.9, 118.6, 107.5, 66.2, 60.1, 45.1, 42.6 and 34.0.

EXAMPLE 5 (7aS,8aR)-4-Benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one(VI)

(5R,6R)-1-Benzyl-5-hydroxy-6-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(V, EXAMPLE 4, 70 g) and THF (1,389 g) is concentrated to remove any bydistillation as a precaution due to reactivity of n-butyllithium towardswater. The mixture is cooled to about −10° and n-butyllithium is addedto make the lithium salt of the starting material with formation ofn-butane byproduct in an exothermic reaction. Benzenesulfonyl chlorideis added slowly to make benzenesulfonate in an exothermic reaction. Thereaction mixture is warmed to 20-25° to complete the reaction. Agueouspotassium carbonate solution is added to scavenge the benzenesulfonicacid and the mixture is stirred to allow crystallization. Water is addedto complete crystallization, the slurry is stirred, cooled and filtered.The crystal cake is washed with water followed by branched chain octaneand dried at 40 to 50° to give the title compound, CMR (CDCl₃) δ 154.1,136.3, 128.6, 127.9, 127.6, 124.3, 120.7, 119.7, 107.4, 46.7, 44.9,40.7, 38.1 and 37.6.

EXAMPLE 6(5R)-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(VII)

A mixture of(7aS,8aR)-4-benzyl-8-methyl-7,7a,8,8a-tetrahydroazireno[2,3-c]imidazo[4,5,1-ij]quinolin-5(4H)-one(VI, EXAMPLE 5, 40 g) t-amyl alcohol (42.4 g) and anhydrous ammonia(1,200 g) is treated with lithium at −33°. After the lithium addition iscomplete, the reaction mixture changes from a yellow slurry to a darkblue mixture. This dark blue mixture is stirred for 30-60 minutes andthen quenched with the addition of water. The cooling is removed fromthe condenser and the ammonia is allowed to evaporate. The residue isdissolved in methanol. This mixture is then concentrated to dryness togive the title compound, which is carried on directly to the next stepwithout isolation.

EXAMPLE 7(5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(VII)

A mixture of(5R)-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one(VII, EXAMPLE 6, 15.0 g, 73.8 mmol) and tetraphosphorus decasulfide(36.1 g, 81.2 mmol) in pyridine (300 mL) is heated in a 125° oil bathunder nitrogen. The reaction is stirred for 5 hr. The mixture is cooledto 20-25° and the pyridine is removed under reduced pressure. Sodiumhydroxide (2.2 N, 200 mL) is added and a vigorous reaction ensues.Additional sodium hydroxide (1 N) is added until a solution is formed.The solution is saturated with sodium chloride and extracted withmethylene chloride (2.5 L, in portions). The organic phase is absorbedonto silicon dioxide (40 g) and purified via column chromatography(silicon dioxide, 225 g; methanol/methylene chloride, 3.5-5.0/96.5-95).The appropriate fractions are pooled and concentrated. The material isrecrystallized from methanol/ethyl acetate/hexanes to give the titlecompound, mp=210-213°; IR (drift) 2940, 2907, 2884, 1483, 1458, 1391,1366, 1354, 1254, 1239, 1229, 895, 762, 734 and 630 cm⁻¹; NMR (300 MHz,CDCl₃) δ 7.12, 7.03, 7.00, 4.30, 3.96, 3.30-3.50, 3.15, 2.88 and 2.57;MS (EI) m/z 219 (M⁺), 190, 189, 187, 186, 164, 163, 155, 145; HRMS (FAB)calculated for C₁₁H₁₃N₃S (MH⁺)=220.0908, found=220.0904.

EXAMPLE 8(5R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionemaleate(IX)

A solution of maleic acid (0.317 g, 2.36 mmol) in a minimal amount ofmethanol (˜1 mL) is added to a mixture of(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione(VIII, EXAMPLE 7, 0.493 g, 2.25 mmol) in methylene chloride. Theresulting solid is collected by filtration to give the title compound;mp=195-196°; [α]²⁵D=−60° (c 0.93, methanol); IR (drift) 3140, 3112.3060, 2969, 1627, 1619, 1568, 1481, 1455, 1398, 1389, 1361, 1220, 868and 747 cm⁻¹; NMR (300 MHz, CD₃OD) δ 7.20-7.30, 7.10-7.20, 6.26, 4.49,4.31, 4.05-4.20, 3.28 and 2.83; CMR (100 MHz, DMSO-d₆+CD₃OD) δ 170.4,169.4, 136.6, 131.1, 130.9, 125.1, 122.1, 116.2, 109.6, 53.9, 43.1, 31.9and 27.2; MS (ESI) m/z=220.1 (MH⁺).

What is claimed is:
 1. A method of treating the symptoms of fibromyalgiasyndrome or chronic fatigue syndrome, comprising administering to apatient in need of treatment, a therapeutically effective amount of anactive agent wherein said active agent is a heterocyclic amine-typecompound of formula (A),

or a pharmaceutically acceptable salt thereof, wherein: R₁, R₂, and R₃are independently hydrogen, C₁₋₆ alkyl, C₃₋₅ alkenyl, C₃₋₅ alkynyl, C₃₋₇cycloalkyl, C₄₋₁₀ cycloalkyl- or phenyl-substituted C₁₋₆ alkyl; X ishydrogen, C₁₋₆ alkyl, halogen, hydroxy, alkoxy, cyano, carboxamide,carboxyl, or carboalkoxyl; A is CH, CH₂, CH-halogen, CHCH₃, C═O, C═S,C—SCH₃, C═NH, C—NH₂, C—NHCH₃, C—NHCOOCH₃, C—NHCN, SO₂, or N; B is CH₂,CH, CH-halogen, C═O, N, NH or N—CH₃, or O; n is 0 or 1; and D is CH,CH₂, CH-halogen, C═O, O, N, NH, or N—CH₃.
 2. The method of claim 1wherein, in said formula (A), D is N or NH, and n is
 0. 3. The method ofclaim 1 wherein, in said formula (A), A is CH, CH₂, CHCH₃, C═O, C═S,C—SCH₃, C═NH, C—NH₂, C—NHCH₃, C—NHCOOCH₃, or C—NHCN.
 4. The method ofclaim 1 wherein, in said formula (A), A is CH or C═O.
 5. The method ofclaim 1 wherein said compound of formula (A) is a compound of formula(Aa):


6. The method of claim 1 wherein said compound of formula (A) is(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)-oneor(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one.7. The method of claim 1 wherein said compound of formula (A) is acompound of formula (Ab):


8. The method of claim 1 wherein said compound of formula (A) is(R)-5,6-Dihydro-5-(methylamino)-4H-imidazo[4,5,1-ij]-quinolin-2(1H)one(Z)-2-butenedioate (1:1).
 9. The method of claim 1 wherein said compoundof formula (A) is a compound of formula (Ac), or formula (VIII):


10. The method of claim 1 wherein said compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thione.11. The method of claim 1 wherein said compound of formula (A) is acompound of formula (Ad), or formula (IX):


12. The method of claim 1 wherein said compound of formula (A) is(5R)-5-(methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinoline-2(1H)-thionemaleate.
 13. The method of claim 1 wherein, in said formula (A): R₁, R₂,R₃ are independently hydrogen, C₁₋₆ alkyl, C₃₋₅ alkenyl, C₃₋₅ alkynyl,or C₃₋₇ cycloalkyl; X is hydrogen, C₁₋₆ alkyl, halogen, hydroxy, oralkoxy; A is CH, CH₂, CH-halogen, CHCH₃, C═O, C═S, or C—SCH₃; n is 0;and D is CH, CH₂, CH-halogen, C═O, O, N, NH, or N—CH₃.
 14. The method ofclaim 13 wherein, in said formula (A): R₁, R₂, and R₃ are independtlyhydrogen, C₁₋₆ alkyl, or C₃₋₅ alkenyl; X is hydrogen, C₁₋₆ alkyl, orhalogen; A is CH, CH₂, CH-halogen, CHCH₃, or C═O; and D is N, NH, orN—CH₃.